PROJECT SUMMARY The toxic metal cadmium (Cd) is one of the top ten chemicals of major public health concern identified by the World Health Organization. Cd exerts toxic effects on the kidneys, respiratory and skeletal systems, and long- term exposure is associated with metabolic, cardiovascular and behavioral disorders. We and others have shown that exposure to Cd during early life can lead to disease in adulthood. One of these diseases is non- alcoholic fatty liver disease (NAFLD), characterized by fat accumulation, inflammation and tissue damage in the liver. NAFLD affects 30-40 % of the US adult population, and patients with NAFLD have a higher risk of developing liver cancer. The broad, long-term objectives of this project are to understand the mechanisms that link early life Cd exposure to NAFLD in adulthood, and to use this knowledge to develop strategies that can prevent or reverse this disease. To this end, we have collected data from pregnant women and their children in North Carolina and demonstrated that DNA isolated from newborn cord blood carries molecular `signatures' of Cd exposure. We propose that these signatures play an important role in Cd-induced NAFLD. In the current proposal, we will use mouse and cell culture models to test this hypothesis, and determine how events at the molecular level lead to disease. We propose three specific aims: 1) determine whether the molecular signatures associated with Cd that we observe in humans cause changes to the activity of a set of genes called imprinted genes, which play important roles in liver metabolism; 2) understand how changes to imprinted gene activity lead to NAFLD; and 3) determine whether Cd could cause NAFLD solely through influencing the activity of these genes. We aim to demonstrate that imprinted genes play a central role in linking early life Cd exposure to NAFLD in adulthood, thereby identifying potential markers of disease susceptibility and providing opportunities for treatment prior to disease onset.